The Value of Natural History Studies for Neuromuscular Disease

In order to prepare for drug development in the neuromuscular disease (NMD) field, some researchers are focusing on natural history studies to better understand these rare diseases. Natural history studies are observational in nature, which means that they do not involve an intervention such as testing a new medicine or device. Rather, they are designed to track the natural course of a disease either in untreated people with NMDs or people with NMDs who are receiving the current standard of care.

Understanding rare diseases

Rare diseases, including many NMDs, are defined as conditions that affect fewer than 200,000 people. These diseases are poorly understood, in part because clinicians rarely encounter people affected by them. Natural history studies can help shed light on the signs, symptoms, and course of rare diseases by aggregating clinical information from a relatively large population of affected people. This information may include age, genetic factors, physical signs or symptoms of disease, clinical or laboratory testing results, imaging results, and quality of life measures over a specific period of time. Analysis of these data can help to identify early signs of the disease, define the rate of disease progression, and identify disease complications that people may experience. It may also uncover disease subtypes, which can present with different symptoms and/or rates of progression.

Use in drug development and clinical testing

To design new therapeutics and conduct meaningful clinical trials (CT), comprehensive knowledge of a disease is required. Therefore, information-gathering from natural history studies can be especially valuable for drug development and CT design in the rare disease space. By collecting granular and descriptive data from people with rare diseases, natural history studies can help to identify potential drug targets and inform the development of new treatment, as well as identify populations that may be eligible to participate in CTs.

Importantly, these studies may also help to identify measures that can be used to monitor disease progression in CTs. New biomarkers defined in natural history studies may be used to monitor the health of biological pathways and/or progression of disease and clinical outcome measures validated by these studies may be used to monitor how a person affected by disease feels, functions, or survives.

Finally, natural history studies can also provide comparative data that can be used in CTs. Baseline measurements established in natural history studies may be used to compare effectiveness of potential treatments against the natural progression of the disease. Furthermore, data from natural history studies may be used as an “external” control when the low number of available participants makes it impossible to designate a placebo control group.

Benefits for patient care

Beyond a role in drug development, natural history studies may also benefit care of people with NMDs. The centers that conduct such studies often build up knowledge and expertise that qualify them as disease-specific centers of excellence. Furthermore, the findings of natural history studies can help to understand and evaluate the current standard-of-care practices, and to determine if new management practices or guidelines are needed to improve patient care.

Natural history studies vs. patient registries

Natural history studies are sometimes confused with patient registries because these programs have some commonalities. Like a natural history study, a patient registry collects medical information about people with a particular disease. Patient registries are designed to store and disseminate this information for research purposes and can be an important resource during drug development. The scope of patient registries, however, tends to be broader than that of natural history studies. Natural history studies have the specific goal of tracking disease progression over time, incorporating clinically relevant measures such as levels of disease biomarkers and measures of muscle mass and function. It is worth noting that some patient registries may also function as natural history studies, depending on the type and breadth of information that they collect.

NMD natural history studies

Natural history studies have previously been employed in several NMDs, including Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and have provided data on the cause, duration, and outcome of these conditions, along with insights about the benefits of standard-of-care treatments. The Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS) is the largest prospective (forward-looking) natural history study performed in DMD to date. This study recruited 440 people with DMD, aged 2–28 years, from 20 centers in 9 countries, and followed them for up to 10 years. The majority of affected people (66%) were ambulatory (able to walk) at the first study visit, and most (87%) received glucocorticoid (steroid) therapy during follow-up visits.

An in-depth resource to learn more about the use of natural history studies in the rare disease space can be found here.

Enrolling NMD natural history studies

There are currently dozens of natural history studies for NMDs that are recruiting or enrolling participants in the United States (US). These include, but are not limited to, the following studies:

ALS

Study Title	Locations
Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4 and Other Inherited Neurological Disorders of RNA Processing	National Institutes of Health Clinical Center Bethesda, Maryland, United States
The Pre-symptomatic Familial Amyotrophic Lateral Sclerosis (Pre-fALS) Study	University of Miami Miami, Florida, United States
Clinical Research in ALS Study	University of Miami Miami, Florida, United States
Phenotype, Genotype & Biomarkers in ALS and Related Disorders	Stanford University Palo Alto, California, United States University of California San Diego (UCSD) San Diego, California, United States California Pacific Medical Center (CPMC) San Francisco, California, United States (and 12 more…)
Investigating Complex Neurodegenerative Disorders Related to Amyotrophic Lateral Sclerosis and Frontotemporal Dementia	National Institutes of Health Clinical Center Bethesda, Maryland, United States

Charcot Marie Tooth disease

Study Title	Locations
Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others	Cedars-Sinai Medical Center Los Angeles, California, United States Stanford University Palo Alto, California, United States University of Colorado Hospital Aurora, Colorado, United States (and 14 more…)
Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT	Stanford University Palo Alto, California, United States University of Connecticut/Connecticut Children’s Medical Center Hartford, Connecticut, United States Nemours Children’s Clinic Orlando, Florida, United States (and 8 more…)

Duchenne/Becker muscular dystrophy (DMD/BMD)

Study Title	Locations
Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy	University of Florida Gainesville, Florida, United States Oregon Health and Science University Portland, Oregon, United States Children’s Hospital of Philadelphia Philadelphia, Pennsylvania, United States
Defining Endpoints in Becker Muscular Dystrophy	University of California, Irvine Orange, California, United States University of Colorado Anschutz Medical Campus Aurora, Colorado, United States University of Iowa Iowa City, Iowa, United States (and 7 more…)

Idiopathic inflammatory myopathies

Study Title	Locations
Adult and Juvenile Myositis	National Institutes of Health Clinical Center Bethesda, Maryland, United States NIEHS Clinical Research Unit (CRU) Research Triangle Park, North Carolina, United States
Study and Treatment of Inflammatory Muscle Diseases	National Institutes of Health Clinical Center Bethesda, Maryland, United States
Sporadic Inclusion Body Myositis Natural History Study	University of California, Los Angeles Los Angeles, California, United States University of California, Irvine Orange, California, United States University of Colorado Aurora, Colorado, United States (and 10 more…)
Studies of the Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases Including Juvenile Dermatomyositis	National Institutes of Health Clinical Center Bethesda, Maryland, United States
Environmental Risk Factors for the Anti-synthetase Syndrome	National Institutes of Health Clinical Center Bethesda, Maryland, United States NIEHS Clinical Research Unit (CRU) Research Triangle Park, North Carolina, United States

Limb-girdle muscular dystrophy (LGMD)

Study Title	Locations
Natural History of Limb Girdle Muscular Dystrophy Type 2A and Type 2E	Nationwide Children’s Hospital Columbus, Ohio, United States
A Study of the Natural History of Participants With LGMD2E/R4, LGMD2D/R3, and LGMD2C/R5, ≥ 4 Years of Age, Who Are Managed in Routine Clinical Practice	Barrow Neurological Institute Phoenix, Arizona, United States Arkansas Children’s Little Rock, Arkansas, United States University of California San Diego La Jolla, California, United States (and 23 more…)
Limb Girdle Muscular Dystrophy Type 2E Recruitment Study	Nationwide Children’s Hospital Columbus, Ohio, United States
Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy (LGMD)	University of California Irvine Irvine, California, United States The University of Colorado Anschutz Medical Campus Aurora, Colorado, United States University of Florida Gainesville, Florida, United States (and 8 more…)

Mitochondrial disease

Study Title	Locations
The Natural History Study of Mitochondrial NeuroGastroIntestinal Encephalopathy (MNGIE)	Columbia University New York, New York, United States
The International Registry for Leigh Syndrome	The University of Texas Health Science Center at Houston Houston, Texas, United States
Mitochondrial Myopathy Rating Scale	Children’s Hospital of Philadelphia Philadelphia, Pennsylvania, United States

Motor neuron disease

Study Title	Locations
Electrical Impedance Myography: Natural History Studies inNeuromuscular Disorders and Healthy Volunteers	National Institutes of Health Clinical Center Bethesda, Maryland, United States
Study of Inherited Neurological Disorders	National Institutes of Health Clinical Center Bethesda, Maryland, United States

Myopathy

Study Title	Locations
A Natural History Study of Patients With GNE Myopathy and GNE-Related Diseases	National Institutes of Health Clinical Center Bethesda, Maryland, United States
Genetic and Physical Study of Childhood Nerve and Muscle Disorders	National Institutes of Health Clinical Center Bethesda, Maryland, United States

Myotonic dystrophy

Study Title	Locations
Trial Readiness and Endpoint Assessment in Congenital Myotonic Dystrophy	Virginia Commonwealth University Richmond, Virginia, United States Pediatric Neuromuscular Research, Children’s Hospital – LHSC London, Ontario, Canada Centro Clinico Nemo Milano, Italy
Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1 (END-DM1)	University of California, San Diego La Jolla, California, United States University of California, Los Angeles Los Angeles, California, United States Stanford University Stanford, California, United States (and 16 more…)

Spinal muscular atrophy (SMA)

Study Title	Locations
Clinical, Molecular and Imaging Biomarkers in Spinal and Bulbar Muscular Atrophy (SBMA)	National Institutes of Health Clinical Center Bethesda, Maryland, United States

 

To learn more about these natural history studies or to identify additional study opportunities, visit clinicaltrials.gov, and use the search boxes to indicate the condition or disease and the type of study (e.g., natural history or observational).

MDA’s work to further natural history studies for NMDs

MDA is committed to furthering research in and therapeutic development for NMDs, including through support of natural history studies. Two ways in which MDA supports these studies are through the funding of (1) research grants, which are given to established investigators to study NMDs and help develop treatments and (2) clinical research network grants (CRNG), which are designed to create a network and infrastructure to promote and accelerate clinical research. Recent MDA-funded grants for natural history studies or related infrastructure include:

Advancing clinical trial readiness in TRPV4 neuropathy (2022-2025)

Dr. Brett McCray, Johns Hopkins University School of Medicine

Charcot-Marie-Tooth disease (CMT) encompasses a group of inherited conditions that cause symptoms of progressive weakness and loss of sensation. CMT is the most common inherited neurological condition worldwide, but there are currently no available treatments to slow progression of any forms of this disease. A subtype of CMT, known as CMT type 2C (CMT2C), is caused by defects in TRPV4, a protein that can open or close to allow calcium to enter cells. The natural progression of CMT2C and readouts of disease progression are not well defined. This project will define markers of disease severity and progression in people with CMT2C, in order to prepare for clinical trials and ultimately establish a treatment.

Inherited Neuropathy Consortium (2022-2025)

Dr. Michael Shy, The University of Iowa

This research consortium is dedicated to developing the infrastructure necessary to evaluate therapies for patients with CMT disease. The investigators in this consortium have developed CMT specific clinical outcome assessments to measure the effects of CMT on adults and children and have identified markers of disease severity in blood, from skin biopsies and also by MRI imaging of muscles.

Muscular Dystrophy Clinical Trial Research Network (2022-2025)

Dr. Jeffrey Statland, University of Kansas Medical Center Research Institute, Inc.

This clinical trial research network is designed to hasten therapeutic development for various muscular dystrophies (MD). The network consists of 15 core US centers, bringing together national leaders in MD research and advancing patient care by providing standardized training and online resources to the next generation of MD researchers. The goal is to work with patients and family members, industry, academics, and drug companies to overcome lingering barriers to drug development. This work will include carrying out trial preparedness studies to validate better biomarkers and clinical outcome assessments for drug approval.